Major histocompatibility complex (MHC) class I molecules, consisting of an α chain and β₂-microglobulin (β2MG), play an important role in immune rejection responses by discriminating self and nonself and are increased by type I interferons during antiviral responses. Interferon tau (IFNτ), the pregnancy-recognition signal in ruminants, is a type I interferon produced by the ovine conceptus between Days 11 and 21 of gestation. In study 1, expression of MHC class I α chain and β2MG mRNA and protein was detected primarily in endometrial luminal epithelium (LE) and glandular epithelium (GE) on Days 10 and 12 of the estrous cycle and pregnancy. On Days 14–20 of pregnancy, MHC class I and β2MG expression increased only in endometrial stroma and GE and, concurrently, was absent in LE and superficial ductal GE (sGE). Although neither MHC class I nor β2MG proteins were detected in Day 20 trophectoderm, β2MG mRNA was detected in conceptus trophectoderm. In study 2, cyclic ewes were ovariectomized on Day 5, treated daily with progesterone to Day 16, received intrauterine infusions between Days 11 and 16 of either control serum proteins or recombinant ovine IFNτ, and were hysterectomized on Day 17. The IFNτ increased MHC class I and β2MG expression only in endometrial stroma and GE. During pregnancy, MHC class I and β2MG gene expression is inhibited in endometrial LE and sGE but, paradoxically, is stimulated by IFNτ in the stroma and GE. The silencing of MHC class I α chain and β2MG genes in the endometrial LE and sGE during pregnancy recognition and establishment may be a critical mechanism preventing immune rejection of the conceptus allograft.